The renin-angiotensin system (RAS; also designated as renin-angiotensin aldosterone system, RAAS) is a key regulator of cardiovascular functions as well as for the balance of electrolytes and for maintaining body fluid volume, and a determinant of blood pressure (cf., for example, E. Lonn, Can. J. Cardiol. 20 (Suppl. B) (2004), 83B; I. A. Reid, Am. J. Physiol.: Advances in Physiology Education 20 (1998), S236). It acts via the effects of angiotensin II, an octapeptide hormone, which binds to angiotensin receptors. The formation of angiotensin II involves two main steps. In the first step, renin (EC 3.4.23.15; formerly EC 3.4.99.19 and EC 3.4.4.15), a 340 amino acid aspartyl proteinase, cleaves angiotensinogen to form the biologically inactive decapeptide angiotensin I. In the second step, angiotensin I is converted into angiotensin II by the zinc-dependent protease angiotensin-converting enzyme (ACE). Renin is produced in the juxtaglomerular cells of the kidney primarily in the form of the biologically inactive prorenin. Its release from the kidney and activation and subsequent RAS activation in normotensive humans is stimulated by sodium or volume depletion, or by a reduction in blood pressure.
RAS activity is the principal determinant of several pathological states since angiotensin II, the major effector molecule of this system, increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating the sodium-retaining hormone aldosterone from the adrenal glands, accompanied by an increase in extracellular fluid volume, as well as having growth-promoting effects on vascular, cardiac and renal tissues which contribute to end-organ damage.
Pharmacological blockade of the RAS is an established way of treating various diseases, for example hypertension (cf., for example, Handbook of Hypertension, W. H. Birkenhäger et al. (ed.), Elsevier Science Publishers, Amsterdam (1986), vol. 8, 489). However, the therapeutic response achieved with the currently used types of RAS blockers, ACE inhibitors and angiotensin receptor blockers, although efficacious, is limited. This may be due to the rise in renin which is induced by these agents and results in an increase in angiotensin I which can be converted into angiotensin II via other pathways than by means of ACE. An inhibition of renin, which controls the initial and rate-limiting step in the RAS by catalyzing the cleavage of the Leu10-Val11 peptide bond of angiotensinogen resulting in the formation of the angiotensin peptides, would inhibit the complete RAS and thus be more efficient. Furthermore, whereas inhibition of ACE also affects the level of other peptides which are cleaved by ACE such as bradykinin, for example, which is associated with side effects of ACE inhibitors like cough or angioedema, renin is specific in that angiotensinogen is its only natural substrate. Inhibition of renin thus offers a specific and powerful way of lowering blood pressure (cf. M. Moser et al., J. Clin. Hypertension, 9 (2007), 701) as well as providing organ protection of organs such as the heart, kidney and brain and, besides for treating hypertension, thus is useful for treating disorders of the cardiovascular system, such as heart failure, cardiac insufficiency, cardiac failure, cardiac infarction, cardiac hypertrophy, vascular hypertrophy, left ventricular dysfunction, in particular left ventricular dysfunction after myocardial infarction, restenosis and angina pectoris; renal diseases, such as renal fibrosis, renal failure and kidney insufficiency; diabetes complications, such as nephropathy and retinopathy; glaucoma; and cerebral afflictions, such as cerebral hemorrhage, for example (with respect to the effect of the RAS on renal diseases and cardiac damage, cf., for example, U. C. Brewster, Am. J. Med. 116 (2004), 263; J. Gaedeke et al., Expert Opin. Pharmacother. 7 (2006), 377; B. Pilz et al., Hypertension 46 (2005), 569).
A large number of peptidic and peptidomimetic inhibitors of human renin with various stable transition-state analogues of the scissile peptide bond have been developed since about 1980 and contributed to the validation of renin as a therapeutic target (cf., for example, B. B. Scott et al., Curr. Protein Pept. Sci. 7 (2006), 241; J. Maibaum et al., Expert Opin. Ther. Patents 13 (2003), 589). However, these compounds generally suffer from deficiencies such as insufficient bioavailability (cf. H. D. Kleinert, Cardiovasc. Drugs Therapy 9 (1985), 645) or duration of action, or high cost of production. Recently, an orally active renin inhibitor, aliskiren (cf. Drugs Fut. 26 (2001), 1139; J. Wood et al., J. Hypertens. 23 (2005), 417; M. Azizi et al., J. Hypertens. 24 (2006), 243) has been marketed. But the property profile of aliskiren is not yet ideal, for example with respect to oral bioavailability, and a particular drawback of aliskiren is its complex molecular structure with four chiral centers and its multistep synthesis. Thus, there is still a great need for new, non-peptidic small molecule renin inhibitors which exhibit favorable properties, for example with respect to oral bioavailability or low molecular complexity and simple synthetic access. The present invention satisfies this need by providing the renin-inhibiting cyclic (aza)indolizinecarboxamides of the formulae Ia and Ib.
Various indolizine and azaindolizine derivatives have already been described. For example, certain indolizine derivatives, i.e. compounds containing the bicyclic ring system that is present in the compounds of the formulae Ia and Ib in case Y is a carbon atom, are described in WO 2004/054507, which relates to inhibitors of PDE4 useful for the treatment of diseases such as cancer or inflammatory disorders, or in WO 2006/136859, which relates to ligands of the CRTH2 receptor useful for the treatment of respiratory diseases. Certain 5-azaindolizine, or pyrrolo[1,2-b]pyridazine, derivatives, i.e. compounds containing the bicyclic ring system that is present in the compounds of the formulae Ia and Ib in case Y is nitrogen atom, are described in EP 1085021, which relates to inhibitors of sPLA2 useful for the treatment of diseases such as septic shock or adult respiratory distress syndrome, or in WO 2005/030144, which relates to inhibitors of protein kinases useful for the treatment of proliferative disorders, such as cancer, and inflammatory disorders. The indolizinecarboxamides and azaindolizinecarboxamides of the present invention, wherein the amide nitrogen atom is a ring member of a 1,4- or 1,5-diazacycloalkane ring system, one of the carbon atoms in the 5-membered ring of the (aza)indolizine ring system, which is adjacent to a fusion position, carries a cyclic group, and the carbon atom in the 5-membered ring of the (aza)indolizine ring system which is not adjacent to the fusion positions, is linked via a carbon atom to a (hetero)aromatic group, have not yet been disclosed.